title: Peripheral blood mononuclear cell gene expression profiles predict poor outcome in idiopathic pulmonary fibrosis.
abstract: We aimed to identify peripheral blood mononuclear cell (PBMC) gene expression profiles predictive of poor outcomes in idiopathic pulmonary fibrosis (IPF) by performing microarray experiments of PBMCs in discovery and replication cohorts of IPF patients. Microarray analyses identified 52 genes associated with transplant-free survival (TFS) in the discovery cohort. Clustering the microarray samples of the replication cohort using the 52-gene outcome-predictive signature distinguished two patient groups with significant differences in TFS. We studied the pathways associated with TFS in each independent microarray cohort and identified decreased expression of "The costimulatory signal during T cell activation" Biocarta pathway and, in particular, the genes CD28, ICOS, LCK, and ITK, results confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A proportional hazards model, including the qRT-PCR expression of CD28, ICOS, LCK, and ITK along with patient's age, gender, and percent predicted forced vital capacity (FVC%), demonstrated an area under the receiver operating characteristic curve of 78.5% at 2.4 months for death and lung transplant prediction in the replication cohort. To evaluate the potential cellular source of CD28, ICOS, LCK, and ITK expression, we analyzed and found significant correlation of these genes with the PBMC percentage of CD4(+)CD28(+) T cells in the replication cohort. Our results suggest that CD28, ICOS, LCK, and ITK are potential outcome biomarkers in IPF and should be further evaluated for patient prioritization for lung transplantation and stratification in drug studies.
authors.affiliation: Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jose D
authors.initials: JD
authors.lastname: Herazo-Maya
authors.forename: Imre
authors.initials: I
authors.lastname: Noth
authors.forename: Steven R
authors.initials: SR
authors.lastname: Duncan
authors.forename: Sunghwan
authors.initials: S
authors.lastname: Kim
authors.forename: Shwu-Fan
authors.initials: SF
authors.lastname: Ma
authors.forename: George C
authors.initials: GC
authors.lastname: Tseng
authors.forename: Eleanor
authors.initials: E
authors.lastname: Feingold
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Juan-Guardela
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Richards
authors.forename: Yves
authors.initials: Y
authors.lastname: Lussier
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: Rekha
authors.initials: R
authors.lastname: Vij
authors.forename: Kathleen O
authors.initials: KO
authors.lastname: Lindell
authors.forename: Jianmin
authors.initials: J
authors.lastname: Xue
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Gibson
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D016000:Cluster Analysis; D015331:Cohort Studies; D020869:Gene Expression Profiling; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics* / Q000628:therapy*; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D018106:CD28 Antigens; D015704:CD4 Antigens